IRP Focus: Biomedical Engineering & Biodesign: Research Projects

The Vanderlick research team is partnering with other research groups across Yale to develop such systems, using naturally motive cells as transportation vehicles. One of the most promising and exciting research directions is the use of spermatozoa as the motive cell fleet, delivering cargo such as RNA or proteins directly to an oocyte at the moment of fertilization. This work is being carried out in collaboration with Yale School of Medicine researchers.

Of course, the largest and most diverse fleet of motile cells belongs to the bacterial world, and Vanderlick’s team and collaborators in SEAS are also investigating methods to couple liposome and polymersomes to the complex outer membranes of selected prokaryotic cells. Potential applications here abound, from bioremediation in soils to oil clean-ups in the ocean.

Further reading: http://eshre2011.congressplanner.eu/showabstract.php?congress=ESHRE2011&...

In a step toward uncovering how these structures form, a team of Yale engineers, physicists, and evolutionary biologists discovered that the color-producing structures in feathers appear to self-assemble in much the same manner as materials undergoing phase separation: Bubbles of water form in a protein-rich soup inside the living cell and are replaced with air as the feather grows, creating a structure similar to that of beer foam.

This research has important implications for the role color plays in birds’ plumage, as the color produced depends entirely on the precise size and shape of these nanostructures. But mechanical engineering professor Eric Dufresne is also interested in the potential technological applications of the finding. He is leading a team that is mimicking the approach to make a new generation of optical materials in the lab.

Publications:
Soft Matter, Advanced Materials.

In the news:
Bird Feathers Produce Color Through Structure Similar to Beer Foam

They have shown bulk metallic glasses to be superior to other materials used in biomedical implants. BMGs exhibit an excellent combination of properties and processing capabilities desired for versatile implant applications, from stents to bone replacement. Unlike most metals, BMGs have an amorphous structure that yields many advantages: high strength (three times that of steel), elasticity, corrosion resistance, and durability. Most notable, they can be molded like plastics with nanoscale precision and complex geometries.

The Yale Engineering collaborators now are putting the outstanding properties of bulk metallic glasses to the test. So far, they have shown that BMGs can, indeed, be implanted in the human body. And in vitro and in vivo study results indicate that the BMGs are compatible with cell growth and tissue function.

Publications:
JOM, Nature

In the news:
New Material for Biomedical Applications Offers Superior Properties
Yale Engineers Revolutionize Nano-device Fabrication Using Amorphous Metals

Chemical and environmental engineers in the Wilson Lab are integrating experimental and computational modeling approaches to design synthetic electron transfer systems. They began by deconstructing Marcus Theory and translating it into a design algorithm for building proteins that are capable of accepting and donating electrons. To accomplish this, the Wilson Lab modeled protein energetics—analogous to stability analysis of buildings whereby civil engineers use accurate computer models to evaluate designs before they are built—using Yale’s Bulldog high-performance-computing clusters. With blueprints in hand, the experimental nano-scale construction work commenced. To date, the team has succeeded in designing functional proteins that propagate electrons and continues toward the goal of perfecting biological mimics.

The potential applications of the work are numerous and exciting. Synthetic electron transfer systems could eventually be used to generate energy in the human body, for instance by mimicking cellular respiration, or in products such as exterior house paints that could imitate photosynthesis to capture and translate light to power the home.

Mechanical engineering & materials science professor Jan Schroers and his colleagues are known for their work on a class of materials called bulk metallic glasses. In the past, Schroers' five-person team spent a year and $500,000 to develop a single new bulk metallic glass. The process entailed weighing and combining various amounts of metals such as gold, silver, palladium, copper, and silicon, putting the combination into a vacuum, and characterizing the result. Working fast, the team produced one new alloy per day, and produced one combination a day for a year to come up with the one that could be blow-molded as a bulk metallic glass.

Now, with their massively parallel approach that sprays four different metals in various ratios onto a substrate, they can process 750 new combinations in a day. They are systematically creating large composition libraries of materials and characterizing them to find properties of interest. The vast stores of information will enable the engineers to produce stronger experimental data points to compare their theories against, and scale up materials development to a pace not seen before.

With a focus on whole arteries and aneurysms, the Humphrey team tackles the problem as a mechanobiological one, aiming to understand the mechanical stimulus and subsequent biological response at the cellular level that manifests at the tissue and organ level. Access to such a tool could create a new niche for biomedical engineers. Because the computational models that the Humphrey engineers are developing would likely be too sophisticated for a general practitioner to employ, they could create a demand for engineers in the clinical environment who would be able to interface with the data and offer interpretations to the physician.

Further reading:

Humphrey JD, Taylor CA (2008) Intracranial and abdominal aortic aneurysms: Similarities, differences, and need for a new class of computational models. Ann Rev Biomed Engr 10: 221-246.

Taylor CA, Humphrey JD (2009) Open problems in vascular mechanics: Hemodynamics and arterial wall mechanics. Comp Meth Appl Mech Engr 198: 3514-3523.

Bazilevs Y, del Alamo JC, Humphrey JD (2010) From imaging to prediction: Emerging non-invasive methods in pediatric cardiology. Prog Ped Card 30: 81-89.

Electrical Engineering Professor Mark Reed is leading a Yale team that is collaborating with a team in the Physics Division at Oak Ridge National Laboratory led by Predrag Krstic to take an innovative approach to the problem. The partnership is employing an ion trapping method that uses oscillating electric fields to confine charged particles to a nanometers-sized space.

Until now, this method, known as a “Paul trap,” has only been used to isolate particles in a vacuum. But Reed, Krstic, and colleagues are using ion-trapping to confine micrometer-sized charged polystyrene beads in aqueous solution to an accuracy of 10s of nanometers. They’ve demonstrated proof-of-principle on test beads recently. Next, they intend to reduce the device size further, to isolate nanometer-sized particles, and eventually to confine DNA. The team hopes to have a working DNA molecule trap within a few years. Analyzing nucleic acids that way could enable quicker, less costly disease diagnostics and treatment, or lead to speedier drug discovery and development.

Publications:

PNAS, June 7, 2011 vol. 108 no. 23 9326-9330 "Paul trapping of charged particles in aqueous solution”

In the News:

Particle Trap Paves Way for Personalized Medicine

Hemant Tagare’s lab is developing algorithms that process biological or medical images to filter out the noise, detect weak signals, and quantify their geometric content. One example is the lab's new effort in creating three-dimensional protein structure from two-dimensional electron microscopy images of the protein. Electron microscopy protein images can be as unclear as the view through a window in a heavy rainstorm, but Tagare’s team takes noisy images of the protein from a variety of angles and processes them to recreate the protein's 3D structure.

In collaboration with Yale professors Frederick Sigworth and Hongwei Wang, the Tagare team is trying to create 3D models that capture the flexible structure of the Dicer protein. Dicer is known for its ability to chop up viral RNA that enters a cell. Modeling its structure could help explain how it does this, and perhaps enable scientists to manipulate or mimic that mechanism in other proteins. What sets Tagare’s efforts apart from engineers elsewhere who are trying to model Dicer is the interdisciplinary approach that relies on close collaboration among biophysicists, biochemists, and image processing experts.

Professor K. S. Narendra and Dr. Stephen Robinson are pursuing a systems theoretic investigation across several areas of neuroscience. Specifically they aim to apply systems theory to inspect and investigate the underlying structures of interaction that exist within these biological systems. Areas of focus include motor control of primitive organisms to the higher order cognitive processes of attention, decision making and synchronization of multiple competing sub-systems.

The goal is to illuminate neural processes from a fresh interdisciplinary perspective, one from which new ideas can be developed to help spur further investigation.

Since 2006, Kumpati Narendra has been collaborating with Peter Reeves (formerly a graduate student at Yale, now at Michigan State University) to apply systems engineering and control theory to the study of human motor control. For the past six years, they have been investigating the effects of control impairments on common conditions such as back pain; more recently they have initiated a study of Parkinson’s Disease (PD).

Research on Back Pain: Interest in controlling human movement has had a long and distinguished history. For instance, Giovanni Alfonso Borelli applied mechanistic theory in the 17th century to predict how much effort was required by muscles in the spine to support the body and external loads. Others developed more sophisticated models of the spine to predict loading on the spine and related it to risk of injury. However, it wasn’t until fairly recently that researchers started to investigate how a motor control error, an unintentional mistake in muscle recruitment, could lead to injury under relatively nominal loads.

To elaborate on this work, Reeves and Narendra examined, in a series of papers, how the central nervous system maintains stability of the spine, and suggested how different types of control impairments may be responsible for back pain.

Publications:

N. P. Reeves, K. S. Narendra, and J. Cholewicki, “Spine Stability: The six blind men and the elephant.” Clinical Biomechanics, vol. 22, pp. 266-274, 2007.

N. Reeves, J. Cholewicki, and K. S. Narendra, “Effects of reflex delays on postural control during unstable seated balance.” Journal of Biomechanics, vol. 42, pp. 164-170, 2009.

N. P. Reeves, K. S. Narendra, and J. Cholewicki, “Spine Stability: lessons from balancing a stick.” Clinical Biomechanics, vol. 26, pp. 325-330, May 2011.

Research on Parkinson’s Disease

Jean Martin Charcot, father of neurology, coined the term Parkinson’s Disease, after a London doctor, James Parkinson, who wrote a paper entitled “An Essay on the Shaking Palsy” in 1817. However, it was only after Sherrington’s work on the nervous system was well established that PD was related to malfunctions within motor circuits.

At present PD is considered as a set of neurodegenerative conditions affecting humans. While no single cause is known to be responsible, it is attributed to the composite result of defects or changes in a number of benign biological processes. Narendra and Reeves believe (following the significant work done at the Hamilton Institute in Maynooth, Ireland), that a systems approach can be a most effective one for the study of PD. They are investigating systematically the effects of small changes in different cellular and metabolic subsystems on motor control. They also believe that the same models can be used to propose corrective actions that may be best suited for an individual.

An alternative form of treatment for PD is through external electrical stimulation. In the 1990s, experiments were described which showed spectacular results using such an approach. Stimulation of the subthalamic nucleus was shown to dramatically reduce Parkinson’s Disease symptoms and restore normal motor function. Since that time, this form of stimulation has evolved into a second form of treating PD. Recently, Narendra and Reeves have also initiated research on the effect of external stimulation on electro-chemical signals in biological systems.

One reason could be randomness. Every cell population exhibits differences–or “noise”–between individual cells, even when the cells are genetically identical and the environment is carefully controlled. Biomedical engineers in the lab of professor Kathryn Miller-Jensen are trying to understand what governs these differences, in order to design more effective therapies. In one innovative approach, the Miller-Jensen team and colleagues at the University of California, Berkeley, are using the HIV virus as an experimental model for studying chromatin—the genetic structures that regulate gene expression. That’s because chromatin modification patterns differ within a population of HIV-infected cells, and Miller-Jensen and her colleagues believe the resulting differences in gene expression may influence whether a virus becomes active or latent.

The engineers suggest their findings may inform efforts to combat diseases by targeting and modifying chromatin, the mechanisms responsible for these phenotypic differences. If all viral infections could be driven towards replication, then all viruses would be susceptible to antiviral drugs. As an alternative strategy, if infection could be forced into a permanent latent state, then the viral genomes could persist without phenotypic consequences. There could be numerous specific therapeutic options for targeting chromatin modification, and the implications of gene expression regulation in treating cancer are also great.

Publications:

Trends in Biotechnology, June 21, 2011, Varying virulence: epigenetic control of expression noise and disease processes

In the News:

Miller-Jensen and Colleagues Propose Targeting Chromatin to Combat Viruses

A team of environmental engineers led by Professor Jordan Peccia is using a high-throughput DNA sequencing technology known as 454 pyrosequencing to unravel the genomes of lipid-rich microalgae. There are several goals of their work. If they can determine how the algae ramp up lipid production, and identify those algae that are most capable of producing lipids, the information could be useful in enhancing biofuel production. In addition, the Peccia team is using the technology to create a genetic library of the hundreds of thousands of species of algae in order to identify those that are ripe for genetic modification for biofuel production and those that are pure, lipid-enriched strains.

Because lipid creation is an energy-intensive process, the algae that are the best producers are also the weakest when it comes to surviving in an environment among competitors. So the Peccia team is also researching how to keep one particularly strong lipid producer, S. dimorphus, growing in a reactor contaminated by other algal species. By making genetic libraries of the algae and bacteria that thrive in a reactor as S. dimorphus dies off, they can trace population declines to particular causes and perhaps devise a solution. They are also exploring ways of promoting S. dimorphus growth, such as increasing CO2 content, which many competing algae species cannot tolerate. With information like that, microalgae may soon reach its true potential as a sustainable biofuel.

In the news:

Microbial Diversity: From Genetic Sequencing to Biofuels

Van Tassel and his group have developed an idea that appears to address this challenge: a thin polymer film biomaterial offering both high rigidity and bioactivity. The approach involves forming the film in the presence of sacrificial nanoparticle templates. The film is first rigidified through a chemical cross-linking procedure; then, the template species are selectively dissolved, leaving behind a pore structure. These pores can then be filled with proteins able to communicate with cells, rendering the film bioactive.

The new approach – part of an ongoing effort toward polymeric thin film biomaterials – achieves mechanical rigidity in conjunction with bioactivity, and, notably, allows for embedding high quantities of biological species without regard to size (previous methods were limited to lower quantities of smaller drug or protein species).

Publications: Advanced Functional Materials